Prevalence of Osteoporosis in Patients with Type 2 Diabetes Mellitus in the Chinese Mainland: A Systematic Review and Meta-Analysis.

Background: Some studies have investigated the prevalence of osteoporosis in patients with type 2 diabetes mellitus (T2DM) in China. However, the results were inconsistent. This review was performed to estimate the prevalence of osteoporosis in T2DM patients in the Chinese mainland and to characterize its epidemiology. Methods: A literature search was conducted utilizing PubMed, Scopus, Web of Science, Cochrane Library, CNKI, Wanfang database from their inception through June 2017. A total of 54 studies evaluating the prevalence rate of osteoporosis in T2DM patients were collected. Prevalence estimates from the individual study were combined utilizing random-effect models in Stata 12.0. Results: The pooled prevalence rate of osteoporosis in T2DM patients was 37.8%. Notably, osteoporosis was more frequent in females than in males (44.8% vs. 37.0%) and was increased with ageing (over 60: 40.1% vs. below 60: 26.5%). Osteoporosis prevalence was higher in less developed areas than in developed areas (41.0% vs. 32.7%) and almost the same between the southern and northern regions (37.6% vs. 38.2%). The prevalence rate between 2010 and 2017 decreased compared with the period between 2001 and 2009 (42.3% vs. 35.6%). Additionally, the meta-regression suggested that gender and age could significantly influence the estimation of prevalence rates respectively (P = 0.011, P = 0.022). Conclusion: Osteoporosis affects more than one-third of T2DM patients in China mainland. Females and older adults more likely require clinical prevention due to a higher prevalence. Further studies are needed to be conducted to incorporate and verify previous results.


Introduction
With the aging population continuing to grow, there has been a significant rise in the prevalence of Type 2 diabetes mellitus (T2DM). It has been observed in practically all regions of the world, with 415 million people suffering from diabetes worldwide (1). In recent decades, people with diabetes in China have increased on a yearly basis. In 2007, there were about 40 million diabetics in China, and it has been estimated that diabetics in China will reach approximately 42.3 million by 2030 (2)(3)(4). By that time, China will replace India as the country with the most diabetes patients worldwide. Diabetes influences the function of multiple organs in the human body, including the heart, brain, kidney, peripheral nerves, eyes, and feet. Additionally, there can also be more than 100 kinds of complications involved with the disease, and it is currently known as the disease with the most complications (5). Throughout recent years, studies on the correlation between diabetes and osteoporosis have been widely recognized by scholars. Both osteoporosis and diabetes are metabolic diseases, and they have a complicated relationship with each other. It is well recognized that type 1 diabetes mellitus can decrease bone mineral density (BMD) and increase the risk of bone fracture (6), while the correlation between T2DM and osteoporosis remains unclear. Therefore, it is necessary for both physicians and patients to be aware of the prevalence rate of osteoporosis in T2DM patients and to learn the relevant characteristics in the diagnosed populations for the sake of early prevention. At present, no systematic review and meta-analysis regarding the prevalence rate of osteoporosis in T2DM patients in China has been conducted. The objective of this review was to acquire reference values for the prevalence of osteoporosis in T2DM patients utilizing the meta-analysis method. We also described the characteristics of T2DM patients with osteoporosis based on a large sample size, which is intended to provide evidence for physicians as well as the health supervision department.

Search Strategy
According to the PRISMA (2009) standard, we searched PubMed, Scopus, Web of science, Cochrane Library, CNKI, Wanfang data for relevant studies (updated until June 6, 2017). Subject retrieval words and keywords were as follows: type 2 diabetes mellitus, diabetes, T2DM, osteoporosis, prevalence, and epidemiological investigation. Literature languages are not limited.

Study Selection
Studies involved in this review met the following criteria: the participants were clinically diagnosed with T2DM in the Chinese Mainland; the study design was a cross-sectional study; the test equipment utilized was the BMD dual-energy X-ray absorptiometry and the parts that were tested consisted of the lumbar or the hip. Notably, the prevalence of osteoporosis in T2DM patients can be directly extracted from literature or indirectly calculated.

Data Collection and Assessment Processes
The retrieved studies were simultaneously and independently screened by two reviewers based on the previously formulated inclusion criteria. The extraction content mainly consisted of the first author, date of publication, diagnostic criteria, sample size, test instrument, test parts, and prevalence. When research reporting positive detection rate of osteoporosis in more than one part was observed, we chose the positive detection rate of the lumbar vertebra to be the standard. After disqualified and repetitive studies removing, the remaining studies were subjected to full-text reading and re-screening. If the information provided were unclear or disputable, the corresponding author of the study would be contacted for a thorough inquiry. Then, decisions of whether to keep the information or discard it would be made. Throughout the course of this process, all disagreements between reviewers were resolved through discussion. Included studies were graded in 7 aspects according to the Combie evaluation tool which is as follows (7): the study design was scientific and rigorous; the data collection method was reasonable; the response rate of participants was reported; the total representativeness of samples were favorable; the research objective and methods were reasonable; the power of the test was reported; the statistical method was correct. "Yes", "no" and "have no idea" were respectively utilized to evaluate each item, which was successively given 1 point, 0 points, and 0.5 points. The total score was 7.0 points (6.0 ～7.0 points, 4.0～5.5 points, and 0～4.0 points were considered to an A, B and C level of quality respectively).

Statistical Analysis
The primary analysis in this review was the pooled prevalence of osteoporosis in T2DM patients. Heterogeneity was evaluated using the Cochran Q statistic (P< 0.10 was considered to be statistically significant) and was quantified using the I 2 index (where I 2 > 30% indicated moderate heterogeneity; I 2 > 50% substantial heterogeneity; and I 2 > 75% considerable heterogeneity). If the I 2 test indicated a value > 50% which reflected significant heterogeneity, then a random-effect model was carried out. Conversely, a fixed-effect model was implemented. The subgroup analysis was conducted based on sex (male or female), average age (younger or older than 60 years old), region (south or north), economic level (developed or less developed) and date of publication (2001～2009 or 2010～2016). Besides, a meta-regression analysis was applied as a means to explore the source of heterogeneity among all the studies. Specifically, the concomitant variable includes the date of publication, the female proportion in subjects, region, sample size, economic level, and average age.
Funnel plot with the proportion as the abscissa and the standard error as the ordinate was adopted to reflect the publication bias directly. Begg's test and Egger's test were both applied to create a qualitative judgment on publication bias. Additionally, the trim and filling method would be utilized to evaluate the stability of the obtained result if necessary. All the above analyses were conducted using the Stata 12.0 version, and all reported P values were two-sided with a statistical significance level of 0.05. Figure 1 outlines the search strategy and the selection process. Of the 539 relevant studies initially identified, 383 duplicated records were removed, and 68 articles were subsequently excluded after reading titles and abstracts due to their irrelevant clinical question or incorrect publication type. After the full-text review of 70 studies, we further excluded 16 studies that did not meet the inclusion criteria. Finally, 54 studies with 13462 diabetic patients were included in the meta-analysis . The majority (79.6%) of the included arti-cles scored greater than 4 points as assessed through the Combie evaluation tool, which indicated high and moderate quality literature. The main characteristics and details of each study are summarized in Table 1.

Pooled Prevalence Rates of Osteoporosis in Diabetic Patients Overall
The pooled prevalence rate of osteoporosis in diabetic patients was 37.8% (95%CI: 33.5%, 42.1%, I 2 =96.8%, P<0.001) (Fig. 2). Subgroup analyses were applied based on sex, average age, region, economic level, and publication year in order to explore the source of heterogeneity.    (Table 2).

Regression Analysis and Publication Bias
Pre-specified meta-regression designated that publication year, areas, sample size, economic level, and quality scores did not affect the merged prevalence. However, sex (P=0.011) and average age (P=0.022) in participants remarkably influenced the overall outcome. Significant asymmetry existed in the funnel plot (Fig. 3). The results of the Begg's test (P = 0.058) and the Egger's test (P ＜ 0.001) lacked consistency, which hinted that publication bias existed (Table3). Therefore, we adopted the trim and fill method to examine the publication bias. The number of trimming and filling study was one after three times of iteration.
The P value presented no reversal result before and after trimming and filling (P<0.001 and P<0.001) as it designated that the results were comparatively stable even though the publication bias existed.

Discussion
In this systematic review, we estimated that in Chinese mainland, (a) the pooled prevalence rate of osteoporosis in diabetic patients is 37.8%, (b) old age and being of the female sex are both factors which correlate with a higher prevalence of osteoporosis and (c) economic level has a potential impact on the prevalence of osteoporosis in T2DM patients. To our knowledge, we are the first to systematically collect and analyze the studies utilizing DXA in T2DM patients. According to the current results, the merged prevalence rate of osteoporosis in T2DM patients was much higher than the prevalence rate of primary osteoporosis in the Chinese Mainland reported by Chen (62). Notably, Chen has suggested that long-term high blood glucose might increase the risk for osteoporosis in diabetic patients largely. Additionally, some pathological 0 .02 .04 .06 .08 Standard error 0 .2 .4 .6 .8 Proportion mechanisms were related to this problem, such as deficiency or disorder of insulin, obesity, sexual hormone disturbance, and diabetic complications (63). In the early stage, Sosa and Wakasugi supposed that diabetes would not significantly impair bone metabolic status (64,65). Recently, Athulya et al. also reported a negative difference in BMD between diabetic and non-diabetic subjects in India (66). Nevertheless, they noticed that the prevalence of osteoporosis was higher in the T2DM group than that in the control group. Based on the results of the regression analysis, gender was a significant risk factor of osteoporosis in T2DM patients. We observed that the prevalence rate of osteoporosis in female T2DM patients (44.8%) was much higher than that in males (37.0%), and that they were higher than the results of primary osteoporosis reported by Chen respectively (62). Furthermore, age was another significant risk factor of osteoporosis in T2DM patients. The prevalence rate of osteoporosis (40.1%) in patients with an average age above 60 was higher than that in patients under 60 (26.5%). This result was consistent with the generally accepted concept that human bone mass would decline with age after reaching a peak. In the subgroup analysis of the region, we did not detect an apparent difference between the prevalence rates of osteoporosis in T2DM patients residing in the southern and northern regions of China (37.6%, 38.2%). However, these two rates were higher than that of primary osteoporosis in the south and north China in Chen's study (south: 23.17%, north: 20.13%) (62). Climates and eating habits, which were regarded as the influential factors of primary osteoporosis, appeared to have little impact on the prevalence rate of osteoporosis in T2DM patients in the south and north of China (67)(68)(69)(70). The subgroup analysis of the economic level manifested that the prevalence rate of osteoporosis (32.7%) in diabetic patients from developed areas was significantly lower than that in patients from less developed regions (41%). Due to the in-equal distribution of medical resources, diabetic patients from developed areas are prone to receive better medical care and afford long-term medical expenses, which overall contributes to a more stable condition of diabetes. On the contrary, a shortage of medical resources and a lower income level may aggravate the condition of diabetes, causing a high prevalence rate of osteoporosis. Notably, economic growth may be one of the primary reasons for the decline in osteoporosis prevalence in T2DM patients after the 2010 period (35.6%) compared with that in patients from 2001 to 2009 (42.3%). Therefore, we inferred that economic development was beneficial in establishing a stable T2DM condition, which is also crucial in preventing diabetic complications such as osteoporosis (71).

Study Limitations
There were some limitations to this review. Firstly, we included 54 studies, but the number of involved participants still proves to be insufficient. Secondly, all patient information was obtained from hospitals and more women than men were involved in this study, which possibly leads to a higher pooled prevalence rate. Thirdly, a majority of included studies lacked the diabetes course information. Consequently, we were unable to analyze the associations between the diabetes course and the prevalence of osteoporosis in the subgroup analyses.

Conclusion
This review demonstrates that osteoporosis is common in T2DM patients. Old age and being of the female sex proved to reflect a higher osteoporosis prevalence. Notably, economic development may favorably decrease the prevalence of osteoporosis in diabetic patients. However, it is necessary to conduct further studies so as to incorporate previous results, into clinical prevention for osteoporosis in T2DM patients.

Ethical considerations
Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.